Expressing recombinant genes encoding mammalian proteins in bacteria or yeast has not always been successful. First, these expression systems have not always properly processed the polypeptide into mature protein. Second, some mammalian genes simply have not been successfully expressed in these systems, probably because of codon choices that are incompatible with cellular RNases. It is preferred in many cases, therefore, to express genes for mammalian proteins in a mammalian expression system.
Many mammalian genes are expressed under the control of a tissue-specific promoter. Thus, it would be necessary to express genomic clones of these genes in the appropriate primary tissue. Unfortunately, most mammalian primary tissue does not grow well in culture. An exception to that is malignant B-lymphocytes (myelomas). These cells also produce immunoglobulins at very high levels. Only limited success has been achieved, however, in expressing non-immunoglobulin genes under the control of their own promoters in myelomas. Banerji et al. (1983) Cell 33: 729-740, discloses the expression of rabbit .beta.-globin gene under the control of a mouse immunoglobulin heavy chain enhancer in myeloma cells. Rice et al. (1983) Proc. Nat'l. Acad. Sci. USA 79: 7862-7865, discloses the production of a murine lymphoid cell line which expresses a foreign immunoglobulin gene and a bacterial marker gene. See also Oi et al. (1983), Proc. Nat'l. Acad. Sci. 80: 825-829.
Transcription enhancer elements are DNA sequences that can act over distances of several kilobases to increase the activity of a promoter in cis, regardless of orientation relative to the promoter. Both heavy and light chain immunoglobulin genes have enhancers. Several reports have appeared in the literature describing the sequence, location, and function of the immunoglobulin .kappa. light chain transcription enhancer element. See Emorine et al. (1983) Nature 304: 447-449; Parslow et al. (1983) Nucleic Acids Res. 11: 4775-4792; Picard et al. (1984) Nature 307: 80-82; Parslow et al. (1982) Nature 299: 449-451; Queen et al. (1983) Cell 33: 741-748; Bergman et al. (1984) Proc. Nat'l. Acad. Sci. USA 81: 7041-7045. The following articles also relate to transcription enhancement elements: Scholer et al. (1986) Science 232: 76-80; Banerji et al. (1981) Cell 27: 299-308; Moreau et al. (1981) Nucleic Acid. Res. 9: 6251; Gruss et al. (1981) Proc. Nat'l. Acad. Sci. USA 78: 943-947; Fromm et al. (1982) J. Mol. Appl. Genet. 1: 457; Gruss et al. (1983) Cell 33: 313; Gillies et al. (1983) Cell 33: 717-728; Neuberger (1983) Embo. J. 2: 1373-1378; Walker et al. (1983) Nature 306: 557-561; Haslinger et al. (1985) Proc. Nat'l. Acad. Sci. USA 82: 8572; Mercola et al. (1984) Science 227: 266-270; Weiher et al. (1983) Science 219: 626-631.
In Parslow et al. (1984) Proc. Nat'l Acad. Sci. USA 81: 2650-2654, and Falkner et al. (1984) Nature 310: 71-74, short nucleotide sequences (an octamer and a decamer, respectively) were reported to be essential elements of the immunoglobulin heavy chain and light chain promoters. The sequences occur, however, in opposite orientations in the two immunoglobulin genes. Parslow et al. (1984) also reported the occurrence of the octamer in HLA-DR genes.
Mason et al. (1985) Cell 41: 479-487, discloses the transformation of myelomas with a human .beta.-globin gene, including the coding sequence and the TATA box, ligated to immunoglobulin heavy chain promoter sequences. The hybrid construction was found to be nonfunctional without the octamer in the heavy chain orientation.
Mattaj et al. (1985) Nature 316: 163-167, discloses that the above octamer sequence occurs in the 5' region of Xenopus U2 gene, and that deletion of the octamer decreases promoter activity 10-20 fold. The octamer occurs in the heavy chain orientation.
Additional articles discussing the octamer include Bergman et al. (1984), supra; Singh et al. (1986) Nature 319: 154-158.